A major contributor to the impact of heart disease is the low level of regeneration exhibited by mammalian cardiac muscle in response to injury. One potential therapeutic strategy is to identify and augment endogenous mechanisms that maintain low baseline turnover of mammalian cardiomyocytes. Here, to identify the mechanisms of successful heart regeneration, I will examine cardiac regeneration in zebrafish. Zebrafish possess the highest capacity for heart regeneration yet identified in a model system, capable of fully regenerating cardiac muscle after 20% of the ventricle is resected. Furthermore, there are many tools and genetic approaches to exploit using zebrafish. During my fellowship, I will pursue a comprehensive understanding of heart regeneration through a variety of cutting edge approaches. First, I will translationally profile the molecular responses to injury and regeneration of several cardiac cell types. This information will generate the first high-resolution molecular signatures for regeneration. Second, I will create a system to observe the dynamic behavior of individual cells during the regenerative process. By employing this system in small molecule screens, I will gain insights into the molecular cues that block or enhance heart regeneration. This work will create inroads toward modifying the capacity for regeneration in mammalian hearts. PUBLIC HEALTH RELEVANCE: My work will provide a detailed understanding of myocardial regeneration and identify important molecular regulators, information that will lead to approaches for comprehending, and possibly enhancing, the limited regenerative response displayed by humans after myocardial infarction.